Feasibility and acceptability of a novel biomedical device to prevent neonatal hypothermia and augment Kangaroo Mother Care in Kenya: Qualitative analysis of focus group discussions and key Informant Interviews.

Hypothermia is a leading newborn complication, especially among premature and/or low birth weight infants. Within low/middle-income countries where incubators and radiant warmers are often in short supply, leading to gaps in the thermal care chain, neonatal hypothermia underlies high rates of newborn morbidity and mortality. Kangaroo Mother Care/Skin-to-skin care is an effective method for prevention of hypothermia in premature and low birthweight babies but can be very burdensome for families and healthcare providers. Our international multidisciplinary team has developed a prototype for a wearable biomedical device ("NeoWarm") to provide continuous thermal care and augment kangaroo mother care practices in low-resource settings. The objective of this study was to assess the feasibility and acceptability of NeoWarm and to obtain user design feedback for an early prototype from among adult end-users in Western Kenya. We performed key informant interviews (n = 17) among healthcare providers and 5 focus group discussions (FGDs) among 3 groups of adult stakeholders of premature babies, including: (1) parents/family members of premature babies aged 6 weeks or less (3 FGDs); (2) healthcare providers of newborns (e.g., nurses; physicians; 1 FGD); (3) community opinion leaders and stakeholders (e.g., traditional birth attendants; pastors; village elders; 1 FGD). Content and thematic analyses of transcripts indicate that NeoWarm is acceptable and feasible in promoting facility-based kangaroo mother care in the Kenyan setting. Novel findings derived from respondents include (1) the ability of the device to potentially overcome several barriers to traditional kangaroo mother care methods and (2) user-driven encouragement to expand the use case of the device to potentially include community-based kangaroo mother care and neonatal transport. User design feedback obtained during the interviews informed several key design iterations for subsequent prototypes of the device.

Pre-operative corticosteroid injection within 1 month of total shoulder arthroplasty is associated with increased risk of periprosthetic joint infection.

INTRODUCTION: Corticosteroid injections (CSI) may increase the risk of peri-prosthetic infections (PJI) following total shoulder arthroplasty (TSA). Our study specifically assessed the risk of PJI in patients who received CSI: (1) less than 4 weeks prior to TSA; (2) 4-8 weeks prior to TSA; and (3) 8-12 weeks prior to TSA. MATERIALS AND METHODS: A national all-payer database was queried to identify patients who underwent TSA with a shoulder osteoarthritis diagnosis from October 1, 2015 to October 31, 2020 (n = 25,422). There were four cohorts: CSI within 4 weeks of TSA (n = 214), CSI 4-8 weeks prior to TSA (n = 473), CSI 8-12 weeks prior to TSA (n = 604), and a control cohort that did not receive CSI (n = 15,486). Bivariate chi-square analyses of outcomes were performed in addition to multivariate regression. RESULTS: A significant increase in PJI risk at 1 year (Odds Ratio [OR] = 2.29, 95% Confidence Interval [CI] = 1.19-3.99, p = 0.007) and 2 years (OR = 2.03, CI = 1.09-3.46, p = 0.016) in patients who received CSI within 1 month of TSA was noted. PJI risk was not significantly increased at any time point for patients who received a CSI greater than 4 weeks prior to TSA (all p ≥ 0.396). CONCLUSION: PJI risk is increased at both 1 and 2 years post-operatively in patients who received a CSI within 4 weeks of TSA. Therefore, TSA should be deferred at least 4 weeks after a patient receives a CSI to mitigate PJI risk. LEVEL OF EVIDENCE: Level III.

Quality by Design-Based Assessment for Analytical Similarity of Adalimumab Biosimilar HLX03 to Humira®.

Quality by design (QbD) is an efficient but challenging approach for the development of biosimilar due to the complex relationship among process, quality, and efficacy. Here, the analytical similarity of adalimumab biosimilar HLX03 to Humira® was successfully established following a QbD quality study. Quality target product profile (QTPP) of HLX03 was first generated according to the public available information and initial characterization of 3 batches of Humira®. The critical quality attributes (CQAs) were then identified through risk assessment according to impact of each quality attribute on efficacy and safety. The anticipated range for each CQA was derived from similarity acceptance range and/or the corresponding regulatory guidelines. Finally, a panel of advanced and orthogonal physicochemical and functional tests and comparison of 6 batches of HLX03 and 10 batches of the reference standard demonstrated high similarity of HLX03 to Humira®, except for slightly lower percentage of high mannosylated glycans (%HM) in HLX03 which had no effect on FcγRIII binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity in human peripheral blood mononuclear cell (PBMC). All above demonstrated the feasibility and efficiency of QbD-based similarity assessment of a biosimilar monoclonal antibody (mAb).

Demonstrating Analytical Similarity of Trastuzumab Biosimilar HLX02 to Herceptin® with a Panel of Sensitive and Orthogonal Methods Including a Novel FcγRIIIa Affinity Chromatography Technology.

BACKGROUND: A biosimilar needs to demonstrate its similarity to the originator reference product (RP) in terms of structural and functional properties as well as nonclinical and clinical outcomes. OBJECTIVES: The aim was to assess the analytical similarity between the trastuzumab biosimilar HLX02 and Europe-sourced Herceptin® (EU-Herceptin®) and China-sourced Herceptin® (CN-Herceptin®) following a quality-by-design (QbD) quality study and tier-based quality attribute evaluation. METHODS: A panel of highly sensitive and orthogonal methods, including a novel Fc gamma receptor IIIa (FcγRIIIa) affinity chromatography technique that enables quantitative comparison of glycan effects on effector function, was developed for the assessment. To ensure the full product variability was captured, ten batches of HLX02 were compared with 39 RP batches with expiry dates from August 2017 to March 2021. RESULTS: The extensive three-way similarity assessment demonstrated that HLX02 is highly similar to the RPs. Furthermore, the %afucose, %galactose, and FcγRIIIa affinity of the RPs were observed to first decrease and then return to the original level in relation to their expiry dates, and the RP batches can be subgrouped by their FcγRIIIa affinity chromatograms. HLX02 is demonstrated to be more similar to the RPs of the high FcγRIIIa affinity group. CONCLUSION: Besides having an overall high analytical similarity to both EU-Herceptin® and CN-Herceptin®, HLX02 is more similar to Herceptin® with high FcγRIIIa affinity, a result that demonstrates the power of the novel FcγRIIIa affinity chromatography technology in biosimilarity evaluation.

Physicochemical and functional assessments demonstrating analytical similarity between rituximab biosimilar HLX01 and the MabThera®.

Development of bio-therapeutics has exhibited exponential growth in China over the past decade. However, no biosimilar drug has been approved in China (CN) due to the lack of a national biosimilar regulatory guidance. HLX01, a rituximab biosimilar developed in China under European Medicines Agency biosimilar guidelines and requirements, was the first such drug submitted for regulatory review in China, and it is expected to receive approval there as a biosimilar product. To demonstrate the analytical similarities of HLX01, CN-rituximab (sourced in China but manufactured in Europe) and EU-rituximab (sourced and manufactured in Europe), an extensive 3-way physicochemical and functional similarity assessment using a series of orthogonal and state-of-the-art techniques was conducted, following the similarity requirement guidelines recently published by China's Center for Drug Evaluation. The results of the similarity study showed an identical protein amino acid sequence and highly similar primary structures between HLX01 and the reference product (RP) MabThera®, along with high similarities in higher order structures, potency, integrity, purity and impurity profiles, biological and immunological binding functions, as well as degradation behaviors under stress conditions. In addition, HLX01 presented slightly lower aggregates and better photostability compared with the RP. Despite slight changes in relative abundance of glycan moieties and heavy chain C-terminal lysine modification, no differences in biological activities and immunological properties were observed between the RP and HLX01. In conclusion, HLX01 is highly similar to CN- and EU-sourced RP in terms of physicochemical properties and biological activities, suggesting similar product quality, efficacy, and safety. The regulatory requirements interpreted and applied towards the HLX01 marketing application sets a precedent for analytical similarity assessment of biosimilar products in China.

Effect of concussion and blast exposure on symptoms after military deployment.

OBJECTIVE: To examine whether blast exposure alone and blast-associated concussion result in similar neurologic and mental health symptoms. METHODS: A 14-item questionnaire was administered to male US Marines on their return from deployment in Iraq and/or Afghanistan. RESULTS: A total of 2,612 Marines (median age 22 years) completed the survey. Of those, 2,320 (88.9%) reported exposure to ≥1 blast during their current and/or prior deployments. In addition, 1,022 (39.1%) reported ≥1 concussion during the current deployment, and 731 (28.0%) had experienced at least 1 prior lifetime concussion. Marines were more likely to have sustained a concussion during the current deployment if they had a history of 1 (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0) or ≥1 (OR 2.3, 95% CI 1.7-3.0) prior concussion. The most common symptoms were trouble sleeping (38.4%), irritability (37.9%), tinnitus (33.8%), and headaches (33.3%). Compared to those experiencing blast exposure without injury, Marines either experiencing a concussion during the current deployment or being moved or injured by a blast had an increased risk of postinjury symptoms. CONCLUSIONS: There appears to be a continuum of increasing total symptoms from no exposure to blast exposure plus both current deployment concussion and past concussion. Concussion had a greater influence than blast exposure alone on the presence of postdeployment symptoms. A high blast injury score can be used to triage those exposed to explosive blasts for evaluation.

Evaluation and treatment of surgical management of silicone mastitis.

Injected liquid silicone continues to be employed by unscrupulous practitioners in many parts of the world for the purpose of breast augmentation. Complications vary; however, inflammation, foreign body reaction, and granuloma formation often lead to painful and disfigured breasts. Furthermore, migrations of silicone to remote tissues cause additional problems. We present a review of cases and propose an updated algorithm for the diagnosis and management silicone mastitis. We describe two representative cases of mastitis cause by injected liquid silicone. Patients uniformly developed inflammation and granuloma formation causing painful and disfigured breasts. Each patient required bilateral mastectomy and breast reconstruction. Although injection of liquid silicone has been condemned by the legitimate medical community for the purpose of breast augmentation, it continues to be illicitly performed and there exists a sizable patient population suffering from the complications of this procedure. Accurate identification requires a high index of suspicion in patients presenting with firm and painful breasts. An aggressive management strategy is recommended in the setting of silicone mastitis due to the risk of obscuring malignancy.

Kinetic Studies of the Reactions of Pentacyanoferrate(II) Complexes with Peroxydisulfate.

Reactions of Fe(CN)(5)L(3-) (L = 4-aminopyridine (4-ampy), pyridine (py), 4,4'-bipyridine (4,4'-bpy), and pyrazine (pz)) with peroxydisulfate, Fe(CN)(5)L(3-) + S(2)O(8)(2-) right harpoon over left harpoon Fe(CN)(5)L(2-) + SO(4)(-) + SO(4)(2-), have been found to follow an outer-sphere electron transfer mechanism. The specific rate constants of oxidation are 1.45 +/- 0.01, (9.00 +/- 0.02) x 10(-2), (5.60 +/- 0.01) x 10(-2), and (2.89 +/- 0.01) x 10(-2) M(-1) s(-1), for L = 4-ampy, py, 4,4'-bpy, and pz, respectively, at &mgr; = 0.50 M LiClO(4), T = 25 degrees C, pH = 4.4-8.8. The rate constants of oxidation for the corresponding Ru(NH(3))(5)L(2+) complexes were also measured and were found to be faster than those of Fe(CN)(5)L(3-) complexes by a factor of approximately 10(2) even after the corrections for the differences in reduction potentials and in the charges of the complexes. The difference in reactivity may arise from the hydrogen bonding between peroxydisulfate and the ammonia ligands of Ru(NH(3))(5)L(2+) and nonadiabaticity observed in the Fe(CN)(5)L(3-) complexes.